(a) Field of the Invention
This invention relates to an improved process for preparing tablets by a modified wet granulation technique; and especially, but not exclusively, tablets which have a high active matter content, in particular, tablets containing poorly compressible medicinally active matter.
(b) Information Disclosure Statement
A variety of substances meant to be taken by humans and other animals (especially, but not exclusively, pharmaceutical substances intended for oral administration) are often formulated as tablets.
The term "tablet" should be sufficiently familiar to require no explanation; but, in case of need, can be defined as follows. As used herein the term "tablet" includes not only tablets proper but also similar discrete bodies, perhaps of other shapes and sometimes known by different names, above all so called "caplets" (i.e. capsule-shaped tablets, which are easier than tablets to swallow) and also such things as lozenges, pills and dragees. The term is also used to refer to mixtures of particulate solid materials, which have been brought together in various ways and finally compressed so that they become compacted into shaped entities able to persist under normal handling conditions but to disintegrate at the desired site, usually within the body and above all in the digestive tract.
Most tablets are intended to be swallowed, and thus must be kept within the maximum bulk limit which (dependent slightly upon its shape) an average person is able and willing to swallow.
The "size" of the tablets they produce is conventionally defined by tabletters in terms not of their bulk but of their weight. There is room for debate as to what precisely is the absolutely maximum "swallowable" size of tablet, which must depend on the shape of the tablet and on the individual who is to swallow it. It is considered that the absolutely maximum "swallowable" size of tablet can be set at a weight of no more than say 1200 milligrams; and many might choose to set it much lower at a weight of not more that say about 850 mg. Whatever weight limit one adopts (be it 850 mg or 1200 mg, or something in between) it follows that any tablet which is to be swallowed must accommodate all its ingredients, not only the active matter but also every other necessary or desirable type of ingredient, within that weight limit. Moreover that consideration not only applies to tablets intended to be swallowed but to some extent also affects tablets of other kinds, because so much of the available tabletting machinery is dimensioned to produce swallowable tablets that it is often in practice most convenient to make other kinds of tablets on the same machinery and thus to the same dimensions.
For most purposes all necessary ingredients can be accommodated within an 850 mg tablet, and certainly within a 1200 mg tablet. There are however situations in which the above discussed overall weight limitation one tablet size creates a hitherto insurmountable obstacle.
In a pharmaceutical context, one can readily appreciate that the dose necessary at any one administration should desirably be given in the fewest possible tablets, thus if possible in just a single tablet. In the relatively rare event that the dose of active matter necessary at any one administration should exceed the maximum swallowable size of tablet, clearly it is then quite impossible for that dose to be contained in just one swallowable tablet. A much more common situation is however that the amount of active matter to be given at any one administration is less than the swallowable maximum, so that notionally it could all be contained within a single tablet and yet, in practice, that till now has proved impossible, because the amount of active matter so closely approaches the swallowable maximum that the balance is not enough to accommodate the tabletting aids (and possibly other ingredients) which are pharmacologically inert but whose presence is vital to the manufacture of a satisfactory tablet when, as so often, the compression characteristics of the active matter are poor.
In the manufacture of tablets, the final compression of each tablet takes place between the punches within a die, after the latter has been filled with the mixture of particulate solid materials, which however before it enters the die has normally been pregranulated. Such differences as exist between conventional tabletting techniques lie primarily in the respective procedures used for preliminary processing of the mixture of particulate solid materials before they enter the die. When all the ingredients, including the active matter, have good compression characteristics, one may be lucky enough to be able to adopt the simplest and cheapest of techniques known as dry granulation, or a modified version thereof involving what is called preliminary slugging. All too often however the compression characteristics of the mixture are so poor, a defect attributable usually to the nature and/or amount of active matter present, that one is driven back as a last resort on the technique known as wet granulation.
There is much art and skill in practicing the wet granulation technique; but, in outline, it involves no more than the incorporation of a granulating fluid into the mixed, powdery tablet ingredients (including at least some tabletting aids) in such an amount and manner as to convert them into a uniform, moist, coherent, non-pasty mass, which then is formed into moist granules of fairly uniform size, usually by forcing the mass through a screen. Thereafter the moist granules are dried and rescreened to break down agglomerates, and finally blended with other tabletting aids so as thus to arrive at the granulate ready for tabletting.
It will be noted that in wet granulation the tablet ingredients besides the active matter also conventionally include other, pharmacologically inert materials, certainly tabletting aids and perhaps also bulking agents. Some of such tabletting aids may be included in the mixed, powdery ingredients before the granulating fluid is incorporated therein, while further tabletting aids may be applied to the surfaces of the granules, and in between them, after the granules have been formed and before the granulate is passed to the tabletting machine.
At this point it should be observed that when the amount of active matter per tablet is small the pharmacologically inert materials conventionally might well include what are here described as bulking agents, that is to say filler type materials which serve no function except to bulk out the mixture so as to make tablets of adequate size; but that is not the kind of situation with which this invention is primarily concerned, and thus mere bulking agents are not intended to be included in the term "tabletting aids" as used herein.
In the kind of situation in which one resorts to a wet granulation technique, thus when the nature and/or amount of the active matter causes the mixture to have poor compression characteristics, it will however usually be necessary to incorporate some appropriate amount of some or all of the conventional types of tabletting aids, namely binders, glidants, lubricants and disintegrants. Broadly speaking:
the binders are substances which help bind the particles of powder together in a form suited to compaction and compression:
the glidants are substances which aid filling of the particles and/or granules into the die before compression;
the lubricants are substances which help the compressed tablets to leave the die; and
the disintegrants are substances which help the tablet to disintegrate, and perhaps dissolve, when it reaches its ultimate destination, usually within the body.
Quite a variety of materials is available to serve each of these functions, some of them more effective than others. Sometimes a given material may be capable of simultaneously performing more than one function; and, of course, all of them cannot help but bulk out the tabletting mixture, even though that perhaps may not be desired. It will therefore be appreciated that one cannot make any wholly reliable predictions about the absolute and relative amounts of each individual binder and/or glidant and/or lubricant and/or disintegrant which should be present. In a successful formulation made by wet granulation one can however as a generalization say that the overall requirement for all four types of tabletting aids will nearly always fall in the range of from 5% to 25% w/w, calculated relative to the weight of the final (dry) powder mass; and indeed the overall percentage of tabletting aids usually need not exceed say 15% w/w.
Even using the conventional wet granulation technique it is however not always possible to achieve a successful formulation, that is, one which on compression of the granulate yields tablets which conform to accepted standards of hardness, fragility, disintegration and uniformity of weight, unless indeed the above indicated overall percentage of tabletting aids is still further increased. The problem does not usually lie with the tabletting aids themselves, for these can be chosen at will from the well tried array of such materials introduced over very many years, and can be relied upon to serve their function admirably, to the extent that they are not prevented from so doing by the nature of the active matter. It is indeed the active matter which is liable to cause tabletting problems, for here there is no freedom of choice--the tabletter must seek to incorporate in his tablet whatever active matter the clinician wants, and if possible in an amount which represents a unit dose suitable at one administration. While some kinds of active matter, at least when present in moderate proportions, will lend themselves readily to compression and compaction into good quality tablets when accompanied only to conventional proportions of tabletting aids others will not and as new kinds of active matter are introduced which have poor compression characteristics and/or as the clinician seeks to prescribe higher dose levels of existing kinds of poorly compressible active matter, the tabletter is faced with fresh problems, sometimes very difficult or indeed impossible to solve within the confines of a single tablet. Where high dosage active matter (or mixtures thereof) with poor compression characteristics must be incorporated into a single tablet, even conventional wet granulation techniques using normal levels of tabletting aids prove inadequate to resolve these problems; yet if one uses still higher levels of tabletting aids, that may well result in a mixture of such bulk volume that the required weight is difficult or impossible to accommodate within the compression die cavity. However, even if the mixture can be so accommodated and tablets compressed, the tablets then may be of such large size that they are difficult to swallow.
An example of a poorly compressible medicinally active substance is paracetamol (also known as acetaminophen). Illustrative of prior procedures for preparing tablets containing paracetamol are those described in British Pat. Nos. 1,287,431, 1,390,032 and 1,410,909.
The Aspro-Nicholas Ltd. British Pat. No. 1,287,431, published Aug. 31, 1972, discloses a process for preparing coated paracetamol particles suitable for direct compression into tablets comprising agitating particles of paracetamol and a binding agent in an aqueous medium to form a slurry and thereafter drying the resultant slurry to obtain discrete particles of paracetamol coated with said binding agent, the amount of binding agent being such that the dried particles are coated with from 2 to 5%, preferably 3 to 4% by weight of said binding agent and the ratio by weight of uncoated particles of paracetamol to the water in said medium being not greater than 5:1.
The Sterling-Winthrop Group Ltd. British Pat. No. 1,390,032, published Apr. 9, 1975, shows the method of preparing a free-flowing granular material suitable for tabletting which method comprises providing an aqueous fluid comprising: (a) more than 80% by weight of an N-acylaminophenol or ester thereof, and (b) dissolved in the aqueous fluid, from 1.5% to 10%, by weight on the weight of component (a), of a water-soluble polymeric organic binder, and spray-drying the aqueous fluid.
The Sterling-Winthrop Group Ltd. British Pat. No. 1,410,909, published Oct. 22, 1975, shows a method of preparing a composition containing paracetamol which is suitable for direct tablet compression, which method comprises rapidly providing an aqueous solution containing paracetamol, and from 1% to 15% by weight on the weight of the paracetamol, of a polymer selected from homopolymers and copolymers of vinyl acetate and vinyl pyrrolidone dissolved in said aqueous solution at a temperature of at least 95.degree. C., and then immediately cooling this solution with gentle stirring and recovering the solid therefrom.
Thus, combination of poorly compressible medicinally active ingredients, such as paracetamol, with tabletting aids, which include polymeric binders, to produce a blend suitable for compression into tablets is known. It is the manner in which this combination is achieved by the process of this invention which is not obvious.
It is the problem of tabletting such poorly compressible kinds of active matter, and especially those which are clinically prescribed at high dosage levels, to which the instant invention pertains. Investigation of that problem led to questioning hitherto prevailing assumptions concerning the procedures employed in the formation of tablets, with the aim of finding some way of making good quality tablets even from poorly compressible kinds of active matter which tablets however contain no more than the unavoidable proportion of tabletting aids which need to be present in "successful" conventional formulations based on easily compressible active matter.
It now has been found surprisingly that by employing a modified version of conventional wet granulation, which for convenience is termed slurry granulation, there is provided a process for manufacturing tablets which achieves this much desired goal.